The purpose of this project is to elucidate the neural mechanisms and principles of treatment of chronic pain syndromes, with particular attention to the drug treatment of pain caused by nerve injury. There is growing evidence from animal studies in NAB and other laboratories that neuropathic pain may be mediated largely by CNS excitation glutamate receptors. The best studied class of these receptors are the N-methyl-d-aspartate (NMDA) receptors, which have profound effects on sensitizing spinal cord sensory neurons. In order to evaluate the clinical relevance of these hypotheses, we have been studying several NMDA receptor antagonists (Ketamine, dextromethorphan, and memantine) in patients with pain caused by diabetic neuropathy, post-herpetic neuralgia, and other neuropathic pain syndromes. We are also carrying out the first trials in humans of an antagonist of another class of excitatory glutamate receptors, AMPA receptors, which are also thought to play a key role in pain perception and neural sensitization. Because of the involvement of glutamate mechanisms in cognition, movement, and emotion as well as in pain, the key clinical challenge in this field is to improve the ratio of analgesia to side effects with the use of various glutamate receptor inhibitors. To facilitate the identification of glutamate receptor antagonists with the most favorable therapeutic ratio in humans, we have developed the intradermal capsaicin model as an experimental model of the central sensitization that occurs in clinical syndromes. Injection of this chile pepper extract causes transient intense firing of peripheral C nociceptors which then sensitizes central sensory neurons to subsequent painful and light touch stimuli. Ongoing and light touch-mediated pain produced by capsaicin and neuropathic pain respond similarly to ketamine. During this year, we completed two studies that further characterize neural mechanisms of pain and improve the efficiency of the capsaicin model, which will facilitate the work of the many academic and industry research groups that are adopting the method.